Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides

UOPP #1290994, VOL 49, ISS 2 Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides Patrizia Ferraboschi, Samuele Ciceri, and Paride Grisenti QUERY SHEET This page lists questions we have about your paper. The numbers displayed at left can be found in the text of the paper for reference. In addition, please review your paper as a whole for correctness. There are no Editor Queries in this paper. TABLE OF CONTENTS LISTING The table of contents for the journal will list your paper exactly as it appears below: Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides Patrizia Ferraboschi, Samuele Ciceri, and Paride Grisenti Organic Preparations and Procedures International, 49:1–85, 2017 Copyright Ó Taylor & Francis Group, LLC ISSN: 0030-4948 print / 1945-5453 online DOI: 10.1080/00304948.2017.1290994 Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides Patrizia Ferraboschi, Samuele Ciceri, and Paride Grisenti Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Universita 5 degli Studi di Milano, Via Saldini 50, 20141 Milano, Italy Introduction Nucleosides, due to their biological role as constituents of nucleic acids, are main targets in the development of analogues aimed at antimetabolite-based therapy. Modified nucleosides can disrupt biological processes causing the death of cancer or virally-infected cells. 10 Fluorinated analogues of biologically active compounds are often characterized by a dramatic change in their activity, compared with the parent molecules. Fluorine, the most electronegative element, is isosteric with a hydroxy group, the C-F bond length (1.35 A) being similar to the C-O bond length (1.43 A). In addition, it is the second smallest atom and it can mimic hydrogen in a modified structure; its van der Waals radius (1.47 A) is intermedi- 15 ate between that of hydrogen (1.20 A) and that of oxygen (1.52 A). The strength of the C-F bond exceeds that of C-H bond and for this reason organofluorine compounds are often biologically and chemically more stable than their corresponding natural compounds. In the case of nucleosides and their analogues, fluorine atoms can be introduced either in the nucleobase or in the sugar moiety. An example of the first type modification 20 is capecitabine1 (N4-pentyloxycarbonyl-50-deoxy-5-fluorocytidine), a 5-fluoropyrimidine nucleoside approved as a drug against colorectal, gastric and breast tumors; gemcitabine2 (20-deoxy-20,20-difluorocytidine) is an example of a nucleoside fluoro-modified in the sugar moiety, approved as a drug against solid tumors. The aim of this review is to discuss the synthesis of antitumor pyrimidine nucleosides 25 containing fluorine atoms in either the nucleobase or the sugar moiety. Because of the ongoing need of new antitumor chemotherapies, over the years many fluorinated pyrimidine nucleosides have been prepared in order to assay their activity. The synthesis of these compounds has thus been driven largely by results on their biological potential. Nonetheless, it is important for experimentalists to be aware of the full range of methods 30 used, whether or not the compounds synthesized have actually demonstrated antitumor activity. It is our hope, then, that researchers investigating fluoropyrimidines for purposes other than their anticancer properties will also find this article useful. Received June 1, 2016; in final form November 15, 2016. Address correspondence to Patrizia Ferraboschi, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Universita degli Studi di Milano, Via Saldini 50, 20141 Milano, Italy. E-mail:[email protected] This work is dedicated to Dr Giuseppe Celasco deceased on May 10, 2016. 1 2 Ferraboschi, Ciceri, and Grisenti I. Fluoropyrimidines 1. 5-Fluorouracil 35 Interest in the fluoropyrimidines stemmed from studies of the metabolism of uracil in rat hepatoma cells. The observation that these cells utilize uracil more avidly than normal rat intestinal mucosa prompted the preparation of fluorinated pyrimidines in order to improve disruption of tumor DNA biosynthesis.3 In 1957 5-fluorouracil (5-FU) 1 was synthesized by Heidelberger et al.,4 with the aim of 40 blocking metabolism in malignant cells. The replacement of a hydrogen atom at C-5 by the fluorine atom modifies the interaction with the active sites of enzymes involved in metabolism. This antimetabolite, although toxic, is still one of the most widely used agents against solid tumors. Its action is due to two different mechanisms:5 after penetration into the cell, 5-FU 1 is transformed into the 5-fluorouridine triphosphate that mimics UTP, is recognized by RNA 45 polymerase and consequently incorporated into RNA. The most significant action, however, is due to the 5-FU conversion into 5-fluoro-20-deoxyuridine (FdUMP) 2, a known inhibitor of thy- midylate synthetase (TS), a key enzyme in the DNA synthesis.6,7 TS, in the presence of methy- lene tetrahydrofolate and deoxyuridine monophosphate (dUMP) 3 forms a ternary complex that catalyzes the substitution of 5-H uracil with a methyl group, affording thymine. If FdUMP 50 2 is present, the above ternary complex is not able to carry out this reaction, due to the presence of fluorine in the 5-position: the formation of TMP 4 (20-deoxythymidine 50-monophosphate), the only nucleotide precursor specific to DNA, is, therefore, blocked (Scheme 1), decreasing the availability of TTP (20-deoxythymidine 50-triphosphate) for DNA synthesis. Scheme 1 Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides 3 Later two additional mechanisms were proposed for 5-FU 1 antitumor activity: the 55 incorporation of 5-FU into DNA and the alteration of the membrane function of 5-FU 1 treated cells. Recent studies indicate that the TS-direct mechanism predominates when 1 is administered at low doses for a prolonged time, whereas the RNA-mediated process is more active following a bolus administration.8–10 Synthesis of 5-FU 1, by construction of the pyrimidine ring, was first realized by Hei- 60 delberger et al. in 19574,11,12 by reaction of a thiourea derivative 5 with the enolate of ethyl a-fluoro, a-formyl acetate 6 which, in turn, was obtained from methyl formate and ethyl fluoroacetate (Scheme 2). Depending on the chosen a-fluoro-b-ketoester the method is also applicable to the synthesis of other 5-fluoropyrimidines. Scheme 2 An alternative method for the total synthesis is the direct fluorination of the pyrimi- 13 65 dine ring of compound 7 by means of trifluoromethyl hypofluorite (CF3OF) proposed by Robins in 1971. In the case of CF3OF in methanol/fluorotrichloromethane an intermediate was formed that, after treatment with triethylamine, afforded 5-FU 1 in 84% yield.13 If the reaction was carried out with CF3OF in trifluoroacetic acid 1 was directly isolated in 85% yield.14 The method proposed by Robins13 is suitable also for the direct introduction 70 of fluorine on preformed nucleosides, for example compound 8 (Scheme 3). Scheme 3 4 Ferraboschi, Ciceri, and Grisenti The mechanism of the reaction with CF3OF in methanol followed by treatment with triethylamine was later investigated by Robins et al.15 who assigned the structure of (§)-cis-5-fluoro-6-methoxy-5,6-dihydrouracil to intermediate 9 that, by treatment with triethylamine, afforded 5-FU 1 (Scheme 4). 76 80 Scheme 4 85 The use of fluorine as fluorinating agent16,17 requires efficient dissipation of the heat of reaction, in order to avoid the destruction of the carbon skeleton of pyrimidine. This result can be achieved by bubbling a mixture of fluorine and an inert gas through a cold liquid, 90 or removing the heat of reaction by carrying out the reaction in the presence of a metal packing or, finally, by addition of very large amount of an inert diluent gas. This last pro- cedure is the most followed and usually fluorine is diluted with an equal amount of nitrogen and then passed through the reaction mixture. 5-FU 1 was obtained in 92.4% yield16 and sublimation at 190C and 1 mm Hg provided a highly pure product.17 95 Xenon difluoride can be used for direct fluorination of the pyrimidine ring but it is diffi- cult to handle due to its high reactivity; in 1980 Kagan et al. realized the direct fluorination 18 of uracil 7 employing C19XeF6, which is much more stable than free xenon hexafluoride. Uracil 7 was the starting material of the above described direct fluorination methods.13–18 In a method patented in 1979,19 cytosine 10 was fluorinated by means of fluorine fluorosulfo- 100 nate (FOSO2F) diluted with nitrogen (60%) affording 5-FU 1 (87.7% yield) (Scheme 5). Scheme 5 Synthesis of Antitumor Fluorinated Pyrimidine Nucleosides 5 Orotic acid20 11 was, instead, the starting material for a synthesis of 5-FU by a com- bination of a fluorination and a decarboxylation (Scheme 6). In the course of the reaction an intermediate was formed that can be converted into 5-fluoro orotic acid 12 (in boiling water) which was, in turn, transformed into 5-FU by heating at 240C. Scheme 6 105 Starting from the methyl ester of uracil 5-carboxylic acid 13 the synthesis of 5-FU 1 was realized in one-pot, in excellent yield (92%), by addition of a reducing agent (sodium bisulfite) aimed to exclude the formation of peroxides by reaction of water with fluorine (Scheme 7).21,22 Scheme 7 A different approach to the synthesis of 1 provided the substitution of the halo atoms of the 2,4,5-trichloropyrimidine or 2,4-dichloro,5-bromopyrimidine 14 by means of potassium fluo- 110 ride at 400C to afford the corresponding 2,4,5-trifluoropyrimidine 15; its treatment with sodium hydroxide in water at 80C gave the desired 5-FU 1.23 The starting 2,4,5-trihalopyrimi- dine 14 was obtained from uracil 7 by reaction with chlorine, or bromine, followed by treatment of the 5-halouracil 16 with phosphoryl chloride (76 or 82%, respectively) (Scheme 8).

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